Favorable Appendicular Skeletal Muscle Mass Changes in Older Patients With Type 2 Diabetes Receiving GLP-1 Receptor Agonist and Basal Insulin Co-Therapy

Abstract

Background And Aims:

Maintaining appendicular skeletal muscle mass is important for maintaining the quality of life of elderly patients with type 2 diabetes. The possibility of GLP-1 receptor agonists for maintaining appendicular skeletal muscle mass has previously been reported. We investigated changes in appendicular skeletal muscle mass, measured by body impedance analysis, in elderly patients who were hospitalized for diabetes self-management education.

Methods:

The study design was a retrospective longitudinal analysis of the changes in appendicular skeletal muscle mass in hospitalized patients over the age of 70 years. The study subjects consisted of consequential patients who received GLP-1 receptor agonist and basal insulin co-therapy or received basal insulin therapy. Body impedance analysis was performed on the day after admission and on the ninth day of admission. All patients received standard diet therapy and standard group exercise therapy 3 times per week.

Results:

The study subjects consisted of 10 patients who received GLP-1 receptor agonist and basal insulin co-therapy (co-therapy group) and 10 patients who received basal insulin (insulin group). The mean change in appendicular skeletal muscle mass was 0.78 ± 0.7 kg in co-therapy group and −0.09 ± 0.8 kg in the insulin group.

Conclusions:

This retrospective observational study suggests the possibility of favorable effects of GLP-1 receptor agonist and basal insulin co-therapy for maintaining appendicular skeletal muscle mass during hospitalization for diabetes self-management education.

Keywords

Sarcopenia appendicular skeletal muscle mass glucagon-like peptide-1 type 2 diabetes

Introduction

The number of patients with type 2 diabetes worldwide is increasing every year, and their age is also on the rise.¹ Skeletal muscle mass, which tends to decrease with age, is more likely to decrease in patients with diabetes; therefore, skeletal muscle mass should be carefully monitored in elderly patients with diabetes mellitus.^2,3 In fact, skeletal muscle mass reduces owing to the effects of diabetes itself.⁴ The loss of skeletal muscle mass due to diabetes can worsen glycemic control,⁴ which can subsequently lead to diabetic complications.⁴ The progression of diabetic complications and poor glycemic control further reduce skeletal muscle mass.⁴

Patients with diabetes and sarcopenia are considered to be prone to postprandial hyperglycemia.⁵ Thus, multiple doses of insulin injection therapy are beneficial for these patients. Reentry and postprandial blood glucose have been reported to be suppressed by GLP-1 receptor agonists and basal insulin co-therapy.⁶

We investigated changes in appendicular skeletal muscle mass, measured by body impedance analysis, in elderly patients who were hospitalized for diabetes self-management education and received a GLP-1 receptor agonist and basal insulin co-therapy or received basal insulin therapy.

Materials and Methods

Study patients

The study design was a retrospective, longitudinal analysis. The study subjects consisted of consequential patients aged >70 years who were admitted to Ayabe City Hospital for Diabetes Self-Management Education, between May 2019 and February 2021, and received glargine/lixisenatide or basal insulin.

All patients received standard diet therapy and standard group exercise therapy 3 times per week. In addition, patients with HbA1c >9% at admission were treated with multiple doses of insulin injections combined with basal insulin or glargine/ lixisenatide . Glargine/lixisenatide has been used since June 2020.

Body impedance analysis was performed on the day after admission and on the ninth day of admission. Among the patients, those whose skeletal muscle mass could not be assessed were excluded.

This study was approved by the local research ethics committee of Ayabe City Hospital (No.H30-08) and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients.

Data collection

Fasting blood glucose, C-peptide, and creatinine levels after overnight fasting in venous blood were measured the day after admission. Hemoglobin A1c (HbA1c) was measured using high-performance liquid chromatography, and the results were expressed in National Glycohemoglobin Standardization Program units. The estimated glomerular filtration rate (eGFR) was calculated using the formula of the Japanese Society of Nephrology. Retinopathy was assessed by chart review and graded as follows: no diabetic retinopathy, simple diabetic retinopathy, or proliferative diabetic retinopathy.⁷ Neuropathy was diagnosed using the criteria for diabetic neuropathy proposed by the Diagnostic Neuropathy Study Group.⁸ Nephropathy was graded as follows: normoalbuminuria, urinary albumin excretion <30 mg/g of creatinine (Cr) (mg/gCr); microalbuminuria, 30 to 300 mg/gCr; and macroalbuminuria, >300 mg/gCr.⁹ Body mass index (BMI) was calculated as body weight in kilograms divided by height in meters squared. We asked patients about the duration of diabetes, smoking status, and alcohol consumption.

Measurement of body composition

The patient’s body composition was determined using a segmented multi-frequency bioelectrical impedance body composition analyzer (Inbody 770; Inbody Japan Inc., Tokyo, Japan).¹⁰ The multi-frequency impedance body composition analyzer was validated and correlated well with dual-energy X-ray absorptiometry.¹¹ Data on body weight (kg), body fat mass (BFM, kg), and appendicular skeletal muscle mass (kg) were collected. Body fat percentage (BFP, %) was expressed as a percentage of BFM (kg) divided by the total body weight (kg).¹² Skeletal muscle mass index (SMI) was calculated by dividing the appendicular skeletal muscle mass (kg) by the patient’s height (meters squared).¹³

Body composition was measured in all patients on the day after admission and on day nine of admission. Changes in body weight, skeletal muscle mass, and fat mass were defined as (each parameter at the time of the examination on the ninth day of admission minus each parameter on the day after admission).

Standard diet therapy and standard exercise therapy during hospitalization

The diet during hospitalization was based on the “Recommendations on Diet Therapy for Japanese Diabetic Patients” of the Japanese Diabetes Association, with total energy calculated as ideal BW × 25 to 30 kcal/kgBW/day, carbohydrates as 50% to 60% of total energy, protein as 1.0 to 1.2 g/kgBW/day, regardless of renal function, and the rest was provided as fat. Additionally, snacks were prohibited during hospitalization. All patients were instructed to perform aerobic exercises. Hospitalized patients were instructed to perform standardized exercise therapies 3 times a week.

Statistical analysis and missing values

The statistical analyses were carried out using JMP version 14.0 software (SAS Institute Inc., Cary, North Carolina). The subjects consisted of 2 groups: the GLP-1 receptor agonist and basal insulin co-therapy and basal insulin therapy groups. Continuous variables are presented as mean (standard deviation [SD]) values, and categorical variables as numbers (%). The statistical significance of the difference between the groups was assessed using the t-test for continuous variables and the χ2 test for categorical variables in the 2 groups. The relationships between changes in appendicular skeletal muscle mass and other variables were examined using regression analyses.

Results

Thirty-two patients (20 men and 12 women) were hospitalized for diabetes self-management education and received basal insulin therapy or GLP-1 RA and basal insulin co-therapy during the study period. Twenty patients (12 men and 8 women) aged >70 years were included in this study (Table 1). Among the study subjects, all 10 patients (5 men and 5 women) in the co-therapy group received iGraLixi. The average age of patients in the basal insulin therapy and co-therapy groups were 76.8 ± 5.4 and 76.7 ± 5.2 years, respectively. HemoglobinA1c levels in the basal insulin therapy and co-therapy groups were 10.0 ± 1.2% and 10.9 ± 1.4%, respectively. The impedance change values in the trunk were −0.1 (0.4) and −1.2 (0.4), respectively, with a significant decrease in the co-therapy group (P = .045). The changes in skeletal muscle mass were −0.09 ± 0.8 and 0.78 ± 0.7 kg, respectively, with a significant increase in the co-therapy group (P = .013). The changes in body fat were −0.12 ± 0.9 and −0.87 ± 0.6 kg, respectively, with a significant decrease in body fat percentage in the co-therapy group (P = .022) (Figure 1). The total amount of insulin did not change, although the combination therapy group had less bolus insulin and more basal insulin.

Table 1.

Baseline characteristics of the study participants.

	Standard therapy	Combination therapy	P
Number	10	10
Age, y	76.8 (5.4)	76.7 (5.2)	.483
Gender, Male	7	5	.361
Duration of diabetes, y	16.8 (10.0)	7.0 (9.3)	.021
Height, cm	157.3 (3.4)	159.8 (3.4)	.600
Weight, kg	60.1 (4.4)	60.0 (4.5)	.492
Skeletal muscle mass, kg	39.5 (35.0)	27.5 (2.1)	.259
Body fat mass, kg	18.2 (3.1)	20.2 (3.1)	.319
Body mass index, kg/m²	24.0 (1.6)	23.7 (1.6)	.456
Smoking status, never, ex, current	5, 2, 3	4, 3, 3	.855
Alcohol, yes	6	8	.326
Retinopathy, NDR, SDR, PDR	8, 2, 0	7, 2, 1	.587
Nephropathy, normal, micro, macro	5, 5, 0	6, 4, 0	.653
Neuropathy, yes	3	4	.515
Hemoglobin A1c, %	10.0 (1.2)	10.9 (1.4)	.080
C-peptide, ng/mL	1.9 (1.0)	2.6 (1.2)	.080
Creatinine, mg/dL	0.8 (0.1)	0.9 (0.1)	.455
eGFR, mL/m/1.73 m²	71.7 (27.1)	70.6 (26.8)	.464
Total insulin dose, U	19.4 (4.9)	18.5 (1.9)	.298
Basal insulin dose, U	5.8 (2.7)	8.1 (2.5)	.032
Bolus insulin dose, U	13.6 (2.6)	10.4 (2.1)	.004
Average of daily steps, step	5150.4 (2329.1)	2508.1 (1649.0)	.005
Change of body weight, kg	−0.19 (1.1)	−0.03 (0.8)	.359
Change of skeletal muscle mass, kg	−0.09 (0.8)	0.78 (0.7)	.013
Change of fat mass, kg	−0.12 (0.9)	−0.87 (0.6)	.022
Skeletal muscle mass of right arm	2.2 (0.2)	2.0 (0.2)	.231
Skeletal muscle mass of left arm	2.2 (0.2)	2.0 (0.2)	.199
Skeletal muscle mass of trunk	18.8 (1.2)	17.9 (1.2)	.301
Skeletal muscle mass of right leg	6.2 (0.5)	6.4 (0.5)	.387
Skeletal muscle mass of left leg	6.1 (0.5)	6.2 (0.5)	.465
Skeletal muscle mass change in right arm	−0.0 (0.0)	0.1 (0.0)	.018
Skeletal muscle mass change in left arm	−0.0 (0.0)	0.1 (0.0)	.026
Skeletal muscle mass change in trunk	−0.1 (0.2)	0.4 (0.2)	.044
Skeletal muscle mass change in right leg	−0.0 (0.1)	−0.0 (0.1)	.315
Skeletal muscle mass change in left leg	−0.1 (0.1)	−0.0 (0.1)	.321
Impedance of right arm	318.8 (44.6)	340.1 (35.1)	.231
Impedance of left arm	321.8 (47.0)	345.4 (34.7)	.199
Impedance of trunk	19.7 (2.7)	23.1 (3.0)	.301
Impedance of right leg	233.0 (30.1)	234.9 (50.4)	.387
Impedance of left leg	236.8 (34.4)	242.6 (39.0)	.465
Impedance change in right arm	1.2 (3.6)	−4.9 (3.6)	.122
Impedance change in left arm	−15.7 (4.1)	−22.5 (4.1)	.131
Impedance change in trunk	−0.1 (0.4)	−1.2 (0.4)	.045
Impedance change in right leg	−5.7 (4.9)	−2.4 (4.9)	.319
Impedance change in left leg	−1.2 (5.1)	1.4 (5.1)	.363

Abbreviations: eGFR, estimate glomerular filtration rate.

Data are given as numbers (percentages), mean (standard deviation).

P value = Standard therapy versus combination therapy Student’s t-test, Pearson’s qui-squared test were performed.

Figure 1.

Comparison of Insulin group and Co-therapy group in change of body weight, skeletal muscle mass and fat mass.

The associations between changes in skeletal muscle mass and metabolic parameters are shown in Table 2. There was an association between changes in skeletal muscle mass and changes in body weight (r = .63, P = .006) and co-therapy (r = .50, P = .035). The average number of daily injections was not significantly related to changes in appendicular skeletal muscle mass (r = −.41, P = .095).

Table 2.

Simple correlation between change of skeletal muscle mass and metabolic parameters.

	r	P
Age	−.11	.665
Gender	−.12	.624
Duration of diabetes	−.15	.540
Height	.06	.813
Weight	−.06	.819
Skeletal muscle mass	−.12	.648
Body fat mass	.01	.981
Body mass index	−.08	.767
Smoking status	.21	.401
Alcohol	−.15	.562
Retinopathy	.15	.560
Nephropathy	−.16	.521
Neuropathy	.09	.734
Hemoglobin A1c	.19	.444
C-peptide	−.05	.840
Creatinine	.16	.515
Total insulin	.02	.947
Basal insulin	.22	.391
Bolus insulin	−.19	.447
Average of daily steps	−.41	.095
Change of body weight	.63	.006
Change of fat mass	−.41	.091
Use of iGraLixi	.50	.035

Gender was defined as women (=0) or men (=1) and smoking status, alcohol, retinopathy, nephropathy, and neuropathy were defined as no (=0) or yes (=1). The relationships between change of skeletal muscle mass and other variables were examined by Pearson correlation and simple regression analyses.

The multiple regression analyses demonstrated that changes in skeletal muscle mass were associated with co-therapy (β = .84, P = .009), after adjusting for age, sex, smoking status, alcohol consumption, height, weight, duration of diabetes, average number of daily injections, total insulin dose, and hemoglobin A1c (Table 3).

Table 3.

Multiple correlation between change of skeletal muscle mass and metabolic parameters.

	Model 1		Model 2		Model 3
	β	P	β	P	β	P
Use of iGraLixi	−.55	.020	−.6	.027	−.84	.009
Age	−.1	.638	−.27	.263	−.77	.014
Gender	.23	.287	.69	.16	.97	.031
Smoking status			−.33	.365	−.53	.066
Alcohol			.33	.221	.7	.010
Height			−.66	.094	−1.14	.008
Weight			−.04	.855	.11	.544
Duration of diabetes					.44	.07
Average of daily steps					−.11	.666
Total insulin dose					.2	.308
Hemoglobin A1c					−.51	.064

Model 1 was adjusted for age and gender. Model 2 included all variables in Model 1 plus smoking status, alcohol, height and weight. Model 3 included all variables in Model 2 plus duration of diabetes, average of daily steps, total insulin dose, and hemoglobin A1c.

No apparent adverse events were observed in the study subjects.

Discussion

The appendicular skeletal muscle mass was maintained during hospitalization in patients receiving co-therapy. Multiple daily injections of insulin therapy are used for patients with diabetes mellitus.¹⁴ In addition, glucagon-like peptide-1 (GLP-1) is a peptide hormone synthesized and secreted by enteroendocrine L cells. It has a number of physiological effects mediated by its receptor and GLP-1 receptor agonists, including enhancement of glucose-induced insulin secretion, increase in beta-cell survival, inhibition of glucagon production, and delayed gastric emptying. In addition, several studies suggest possible, but unclear, effects of GLP-1-based drugs on muscle mass, metabolism, and function.^15,16 GLP-1 receptor agonists and insulin therapy have the potential to increase skeletal muscle mass. In this study, we observed changes in appendicular skeletal muscle mass during hospitalization in patients who received iGraLixi and lixisenatide combined with glargine at a ratio of 1:1.

The effects of GLP-1 on skeletal muscle have been demonstrated in in vitro and in vivo studies. A study that evaluated the effects of GLP-1 on human skeletal muscle cells reported that it induced myogenesis via a cAMP-dependent complex network.¹⁷ In a study using a dexamethasone-induced mouse muscle atrophy model, it was reported that exendin 4 administration improved muscle atrophy by suppressing muscle atrophy genes, such as myostatin and atrogin 1, resulting in increased muscle mass and muscle function.¹⁸ In addition, it has been reported that intravenous administration of GLP-1 increases blood flow by mobilizing microvessels in skeletal muscle in healthy adults, suggesting that GLP-1 may lead to increased skeletal muscle mass due to increased tissue oxygenation.¹⁹

In clinical practice, adequate nutrition is essential for increasing skeletal muscle mass in patients with type 2 diabetes, and there has been concern about sarcopenia, especially in the elderly, due to weight loss caused by the appetite-suppressing effect of GLP-1.²⁰ In this study, no decrease in food intake was observed during hospitalization.

The limitations of this study are as follows. Because this was a retrospective and non-randomized study, we could not fully explain the causal relationship of our findings. Second, the present study was conducted during 1 week of hospitalization; therefore, the long-term effects remain unknown. Third, this study did not evaluate muscle strength and physical fitness, which are directly related to daily life. Fourth, the study did not evaluate exercise during hospitalization, other than the number of steps taken. Finally, we did not evaluate the amount of activity before and after hospitalization, although the difference in activity before and after hospitalization may have affected the change in skeletal muscle mass after hospitalization.

Conclusion

This retrospective observational study implies the possibility of a favorable effect of GLP-1 receptor agonist and basal insulin co-therapy for maintaining appendicular skeletal muscle mass during hospitalization for diabetes self-management education.

Footnotes

Acknowledgements

We would like to thank Editage () for English language editing.

Declarations

ORCID iD

Takafumi Osaka

References

Ogurtsova

da Rocha Fernandes

Huang

, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40-50.

Sugimoto

Tabara

Ikegami

, et al. Hyperglycemia in non-obese patients with type 2 diabetes is associated with low muscle mass: the multicenter study for clarifying evidence for sarcopenia in patients with diabetes mellitus. J Diabetes Invest. 2019;10:1471-1479.

Liccini

Malmstrom

TK.

Frailty and sarcopenia as predictors of adverse health outcomes in persons with diabetes mellitus. J Am Med Dir Assoc. 2016;17:846-851.

Mesinovic

Zengin

De Courten

Ebeling

Scott

. Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship. Diabetes Metab Syndr Obes. 2019;12:1057-1072.

Ogama

Sakurai

Kawashima

, et al. Association of glucose fluctuations with sarcopenia in older adults with type 2 diabetes mellitus. J Clin Med. 2019;8:319.

Terauchi

Nakama

Spranger

Amano

Inoue

Niemoeller

Efficacy and safety of insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi 1:1) in Japanese patients with type 2 diabetes mellitus inadequately controlled on oral antidiabetic drugs: a randomized, 26-week, open-label, multicentre study: the LixiLan JP-O2 randomized clinical trial. Diabetes Obes Metab. 2020;22:14-23.

Mineoka

Ishii

Tsuji

, et al. Relationship between limited joint mobility of the hand and diabetic foot risk in patients with type 2 diabetes. J Diabetes. 2017;9:628-633.

Tesfaye

Boulton

Dyck

, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285-2293.

Hashimoto

Tanaka

Senmaru

, et al. Heart rate-corrected QT interval is a novel risk marker for the progression of albuminuria in people with type 2 diabetes. Diabet Med. 2015;32:1221-1226.

10.

Osaka

Hamaguchi

Hashimoto

, et al. Decreased the creatinine to cystatin C ratio is a surrogate marker of sarcopenia in patients with type 2 diabetes. Diabetes Res Clin Pract. 2018;139:52-58.

11.

Kim

Shinkai

Murayama

Mori

Comparison of segmental multifrequency bioelectrical impedance analysis with dual-energy X-ray absorptiometry for the assessment of body composition in a community-dwelling older population. Geriatr Gerontol Int. 2015;15:1013-1022.

12.

Osaka

Hashimoto

Okamura

, et al. Reduction of fat to muscle mass ratio is associated with improvement of liver stiffness in diabetic patients with non-alcoholic fatty liver disease. J Clin Med. 2019;8:2175.

13.

Woo

Leung

Morley

JE.

Defining sarcopenia in terms of incident adverse outcomes. J Am Med Dir Assoc. 2015;16:247-252.

14.

Asplund

Protein synthesis and amino acid accumulation during development in the rat: dissociation of diaphragm and heart muscle sensitivity to insulin. Horm Res. 1975;6:12-19.

15.

Edwards

Todd

Mahmoudi

, et al. Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes. 1999;48:86-93.

16.

Rizzo

Barbieri

Fava

, et al. Sarcopenia in elderly diabetic patients: role of dipeptidyl peptidase 4 inhibitors. J Am Med Dir Assoc. 2016;17:896-901.

17.

Gurjar

Kushwaha

Chattopadhyay

, et al. Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents. Metabolism. 2020;103:154044.

18.

Hong

Lee

Jeong

Choi

Jun

HS.

Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy. J Cachexia Sarcopenia Muscle. 2019;10:903-918.

19.

Subaran

Sauder

Chai

, et al. GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans. Clin Sci. 2014;127:163-170.

20.

Kawano

Takahashi

Hashimoto

, et al. Short energy intake is associated with muscle mass loss in older patients with type 2 diabetes: a prospective study of the KAMOGAWA-DM cohort. Clin Nutr. 2021;40:1613-1620.